Microbiocidal effects of various taurolidine containing catheter lock solutions.

BACKGROUND & AIMS: We have recently shown that a catheter lock solution containing taurolidine dramatically decreases catheter-related bloodstream infections (CRBSI) in patients on home parenteral nutrition (HPN) when compared to heparin. Since several taurolidine formulations are commercially available, some of which also contain citrate or heparin, we were interested in the effect of these different locks on growth and biofilm formation of fungal, Gram-negative and Gram-positive pathogens that are known to impede HPN treatment. METHODS: Clinical isolates obtained during CRBSI of HPN patients were grown in the presence of catheter locks (2% taurolidine, 1.34% taurolidine-citrate, 1.34% taurolidine-citrate-heparin, citrate and heparin) or phosphate buffered saline diluted in lysogeny broth medium for bacteria and sabouraud liquid medium for yeasts. Biofilm formation, assessed by crystal violet staining, and growth of clinical isolates were determined by optical density measurements. RESULTS: We found that 12.5× diluted solutions of all taurolidine containing formulations completely prevented growth of Escherichia coli, Staphylococcus aureus and Candida glabrata. Growth of these microbes was detected earlier in 1.34% taurolidine-citrate(-heparin) than in 2% taurolidine, while citrate and heparin did not inhibit growth of clinical isolates compared to PBS. No differences in biofilm formation were found between taurolidine containing solutions. CONCLUSION: Taurolidine containing lock solutions prevent growth of fungal, Gram-negative and Gram-positive pathogens. While 2% taurolidine appears to be the most potent in this respect in this in vitro setting, the relevance of the small differences in growth inhibition between the commercially available taurolidine containing lock solutions for clinical practice remains to be established.

Effects of celecoxib on major prostaglandins in asthma.

BACKGROUND: Prostaglandin (PG) D(2) is a pro-inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma. OBJECTIVES: Primarily, to assess whether treatment with the COX-2 selective inhibitor celecoxib inhibited biosynthesis of PGD(2) , monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE(2) , thromboxane A(2) and PGI(2) , also measured as major urinary metabolites. METHODS: Eighteen subjects with asthma participated in a cross-over study where celecoxib 200mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV(1) and airway inflammation as fraction of exhaled nitric oxide (F(E) NO). RESULTS: Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3-day treatment did not cause significant changes in FEV(1) or F(E) NO. CONCLUSION AND CLINICAL RELEVANCE: Biosynthesis of PGD(2) was increased in subjects with asthma and its formation is catalysed predominantly by COX-1. By contrast, COX-2 contributes substantially to the biosynthesis of PGE(2) . The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long-term adverse consequences of COX-2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics.

Increased levels of cysteinyl-leukotrienes in saliva, induced sputum, urine and blood from patients with aspirin-intolerant asthma.

BACKGROUND: A diagnosis of aspirin-intolerant asthma requires aspirin provocation in specialist clinics. Urinary leukotriene E(4) (LTE(4)) is increased in aspirin-intolerant asthma. A study was undertaken to investigate new biomarkers of aspirin intolerance by comparing basal levels of cysteinyl-leukotrienes (CysLTs) and leukotriene B(4) (LTB(4)) in saliva, sputum and ex vivo stimulated blood in subjects with aspirin-intolerant and aspirin-tolerant asthma. The effects of aspirin- and allergen-induced bronchoconstriction on leukotriene levels in saliva and ex vivo stimulated blood were also compared with the effects of the provocations on urinary mediators. METHODS: Induced sputum, saliva, urine and blood were obtained at baseline from 21 subjects with asthma. At a separate visit, 11 subjects showed a positive response to lysine-aspirin inhalation and 10 were aspirin tolerant. Saliva, blood and urine were also collected on the provocation day. Analyses of CysLTs and LTB(4) and the prostaglandin D(2) metabolite 9alpha,11beta-prostaglandin F(2) were performed and the fraction of exhaled nitric oxide was measured. RESULTS: Subjects with aspirin-intolerant asthma had higher exhaled nitric oxide levels and higher baseline levels of CysLTs in saliva, sputum, blood ex vivo and urine than subjects with aspirin-tolerant asthma. There were no differences in LTB(4) levels between the groups. Levels of urinary LTE(4) and 9alpha,11beta-prostaglandin F(2) increased after aspirin provocation whereas leukotriene levels in saliva and ex vivo stimulated blood did not increase. CONCLUSION: These findings support a global and specific increase in CysLT production in aspirin-intolerant asthma. Measurement of CysLTs in saliva has the potential to be a new and convenient non-invasive biomarker of aspirin-intolerant asthma.

Assessment of small health risks based on exact sample sizes.

Exact sample sizes and critical numbers of cases for the rejection of a known event probability (10(-2) to 10(-6)) in favour of an increased probability (1.5- to 50-fold) at levels -alpha;beta- = -0.05; 0.10- and -alpha;beta- = -0.10;0.05- are presented. The numbers are thoroughly validated using the characteristics of the confidence interval for the unknown true event probability. Equivalence is shown to be obtainable for the tolerated maximal value of the relative risk and the upper limit of the confidence interval for the true event probability. Also demonstrated is the use of the tables for planned actions to reduce given empirical risks. In addition, use of the tables is shown for judging results from given data sets.

HLA-associations in Leponex/Clozaril (clozapine)-induced granulocytopenia and agranulocytosis. Statistical viewpoints.

This paper describes a statistical analysis of the simultaneous occurrence of 48 human leucocyte antigens (HLAs) in an attempt to predict whether a patient treated with clozapine will develop granulocytopenia or agranulocytosis. Whereas the numerical results show that use of HLAs does not appear to satisfy the intended purpose, emphasis is placed on the statistical methodology recommended for a problem of this type. Other work in this area is critically discussed.